Several patents have disclosed various methods of producing 2β-substituted methyl penam derivative. For instance, U.S. Pat. Nos. 4,529,592, 4,562,073, & 4,668,514 and EP 97446 discloses a process, which involves treatment of 2β-azidomethyl penam derivatives of the formula (II): wherein R represents a carboxy-protecting group, with acetylene/acetylene derivative or vinyl derivative under high pressure in a sealed reactor and at elevated temperatures followed by deprotection with a suitable reagent to get the β-lactamase inhibitor of the formula (I).
The 2β-azidomethyl penam derivative of the formula (II) was in turn prepared from the 2β-substituted methyl penam derivatives of the formula (III) wherein R represents carboxy-protecting group; X represents chloro or bromo, by treating with sodium azide in aqueous polar aprotic solvents, followed by oxidation.
The above method suffers from the limitation of introducing only very few heterocycles like 1,2,3-triazole group, but not a wide variety of other heterocycles. In addition, the method requires handling of acetylene gas at high pressure and high temperature, which carries inherent hazard owing to its high detonation velocity, thus rendering it non industrial and eco-friendly. Added to it, this process also requires handling of excess sodium azide, leaving behind large quantities of azide for ETP treatment which is hazardous owing to the release of hydrazoic acid as it is a potential explosive and a serious health hazard.
The EP 0273699 discloses a different approach, which involves the preparation of 2β-triazolylmethylpenam derivatives of the formula (IV) wherein R represents carboxy protecting group, n=0, by the treatment of 2β-halomethyl penam derivative of the formula (III) wherein X represents chlorine or bromine; R represents carboxy-protecting group, with 1H-1,2,3-triazole. The product obtained can be oxidized and deprotected to get the 2β-substituted methyl penam derivatives of the formula (I).
EP 306924 discloses a reduction method employing lead compounds like lead chloride or lead bromide to prepare 2β-triazolylmethyl penam derivative of the formula (IV) (n=0-2) from 6,6-dibromo-2β-triazolylmethyl penam derivative of the formula (V). wherein R1, and R2 may be same or different and represent H or bromine; R is a carboxy-protecting group.
In yet another method disclosed in the U.S. Pat. No. 4,895,941, the penam sulfoxide of the formula (VI) wherein R represents carboxy-protecting group, is treated with 2-trimethylsilyl-1,2,3-triazole in a sealed tube at elevated temperatures to give a mixture, which requires purification by column chromatography to isolate the 2β-triazolylmethyl penam derivative of the formula (IV) (n=0).
In most of the methods involved, 2β-halomethylpenam of the formula (III) is used as the key intermediate. This is true with both the azide route and the triazole route discussed above. However, the five-membered 2-halomethyl penam of the formula (III) itself is an unstable intermediate and therefore manufacturing of this intermediate in large quantities and storing is always cumbersome. This intermediate has been found to degrade on storage even at low temperatures in isolated form as well in the solvent from which it is isolated. Thus all the operations related to preparation of this intermediate have to be done rapidly and the isolated intermediate has to be converted to the final product immediately. As a result of these limitations, the scale up in plant always affords less yield and low quality, which ultimately leads to low level of consistency.
All the above described processes are associated with one or more of the following limitations: (i) unstable nature of the key intermediate (ii) use of hazardous and explosive reagents (iii) requirement of high pressures coupled with elevated temperatures—especially with acetylene (iv) use of large excess of sodium azide and its consequent environmental and explosion issues (v) use of highly toxic and polluting compounds of heavy metals like lead, especially in the penultimate stages of pharmaceuticals. These factors affect the consistency in quality and yield of the intermediates and the final product as well as safety on manufacturing scale.
To overcome the foregoing limitations, we were searching for a novel process, which involves stable intermediates and safe reagents/reaction conditions to manufacture 2β-substituted methyl penams. In our laboratory, we conducted extensive research and investigated a variety of synthetic schemes and methodologies to find a novel solution for manufacturing the said penam.
As a result of our continued efforts, we could identify a new route, which employs a cepham moiety unlike the penam derivatives employed so far. The advantage of the application of the six-membered cepham moiety is that it is a stable intermediate unlike the penams employed so far, and therefore utilization of this intermediate would reflect in overcoming the limitations discussed above.
While in all the available literature 2β-chloromethylpenams of the formula (III) were employed to prepare 2β-triazolylmethyl substituted penams of the formula (IV), whereas the present invention relies on ring-contraction phenomenon of converting the six-membered 3-halomethyl cephams of the formula (VII) in to 2β-heterocyclyl methyl penams of the formula (I).